Inhibition of Both the Extrinsic and Intrinsic Death Pathways through Nonhomotypic Death-Fold Interactions
| Autor: | Kartik Mani, Young-Jae Nam, Chang Fu Peng, Yukihiro Hayakawa, Peiyee Lee, Stanley J. Korsmeyer, Anthony W. Ashton, Richard N. Kitsis, Barath Krishnamurthy |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Death Domain Receptor Signaling Adaptor Proteins
Death fold Phenylalanine Recombinant Fusion Proteins Amino Acid Motifs Apoptosis Mitochondrion Models Biological Receptors Tumor Necrosis Factor Adenoviridae Cell Line Mice Proto-Oncogene Proteins Two-Hybrid System Techniques Animals Humans Myocytes Cardiac FADD fas Receptor Molecular Biology Caspase Cells Cultured Death domain bcl-2-Associated X Protein Arc (protein) biology Cell Biology Precipitin Tests Cell biology Protein Structure Tertiary Rats Amino Acid Substitution Proto-Oncogene Proteins c-bcl-2 Caspases biology.protein Chromatography Gel Death effector domain |
| Zdroj: | Molecular Cell. 15(6):901-912 |
| ISSN: | 1097-2765 |
| DOI: | 10.1016/j.molcel.2004.08.020 |
| Popis: | Death-fold domains constitute an evolutionarily conserved superfamily that mediates apoptotic signaling. These motifs, including CARD (caspase recruitment domain), DD (death domain), and DED (death effector domain), are believed to exert their effects solely through homotypic interactions. Herein we demonstrate that the CARD-containing protein ARC engages in nontraditional death-fold interactions to suppress both extrinsic and intrinsic death pathways. The extrinsic pathway is disrupted by heterotypic interactions between ARC's CARD and the DDs of Fas and FADD, which inhibit Fas-FADD binding and assembly of the death-inducing signaling complex (DISC). The intrinsic pathway is antagonized by ARC-Bax binding, involving ARC's CARD and the Bax C terminus. This inhibits Bax activation and translocation to the mitochondria. Knockdown of endogenous ARC facilitates DISC assembly and triggers spontaneous Bax activation and apoptosis. Conversely, physiological levels of ARC suppress these events. These studies establish a critical role for nonhomotypic death-fold interactions in the regulation of apoptosis. |
| Databáze: | OpenAIRE |
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